Table 2 Novel key genomic alteration associated with prognosis in adult ALL

IKZF1 deletions and sequence mutations

15% of pediatric B-ALL cases; 70% of BCR-ABL1 + lymphoid leukemia, and 30% of high-risk BCR-ABL1-like B-ALL

IKZF1 alterations are associated with poor outcome in both BCR-ABL1–positive and negative ALL cases, and triple the risk of treatment failure. IKZF1 status is an independent risk factor at a multivariable analysis of established prognostic factors.

CRLF2 rearrangement (as IGH@-CRLF2 or P2RY8-CRLF2)

Up to 16% of pediatric and adult B-ALL; >50% Down syndrome (DS) ALL

Concomitant JAK1/2 mutations in >50% of cases; associated with IKZF1 alteration and poor outcome, particularly in non-DS-ALL.

JAK1/2 mutations

Up to 10% of high-risk BCR ABL1-like B-ALL; 18–35% of DS ALL

Almost all cases of B-ALL with JAK1/2 mutations harbor concomitant CRLF2 rearrangement, associated with poor outcome; may be responsive to JAK inhibitors.

CREBBP deletions and sequence mutations

19% of relapsed B-ALL

Associated with glucocorticoid resistance; Resulted in impaired acetylation of histone targets; histone deacetylase inhibitors may be useful.

CDKN2A/B deletions

~30% of B-ALL; 47% of relapsed BCR-ABL1-ALL;

Associated with poor outcome in terms of overall survival, and incidence of relapse in adult BCR-ABL1-positive ALL; controversial prognosis in other B-ALL subtypes.

TP53 deletions and sequence mutations

Up to 12% of B-ALL;

Enriched at relapse and associated with non-response to chemotherapy and poor event-free survival and overall survival.

PHF6 deletions and sequence mutations

38% of adult T-ALL cases

Associated with reduced overall survival.

PTEN deletions and sequence mutations

6–8% of T-ALL

Associated with poor response to chemotherapy and resistance to pharmacological inhibition of NOTCH1

N/K-RASmutations

10% of adult T-ALL

N/K-RASmutations demonstrated trends to a worse outcome.

NOTCH1 mutations

~50% of T-ALL

Associated with favorable outcome

FBXW7 mutations

12-24% of adult T-ALL

Associated with favorable prognosis due to enhanced glucocorticoid receptor α levels and steroid sensitivity

NT5C2 mutations

19% of relapse T cell ALL and 3% of relapse B-precursor ALL

NT5C2 mutant proteins increase nucleotidase activity in vitro and drive resistance to treatment with nucleoside analog therapies